Cognitive function is recognized to diminish with normal aging. For many years, diminishing cognitive function was believed to be, at least in part, a reflection of neuron loss across life span. More recent studies, however, utilizing contemporary stereological quantification techniques have provided compelling evidence that such neuron loss rarely takes place during the course of normal aging. In the face of relative stability of neuron numbers, age-related functional changes are likely due to a change in the synaptic interactions of the existing neurons and their postsynaptic targets at a molecular, physiological, and/or structural level. Considerable evidence exists for structural changes as the brain ages and the presence of such structural changes across the life span is consistent with age-related changes in the biological mechanisms that serve to maintain the structure of synaptic connections. Both the pre-synaptic and post-synaptic elements have been shown to be influenced by trophic factors such as IGF-1. Not only does IGF-1 promote dendritic elaboration, provide synaptic support and maintenance, and stimulate neurogenesis, it has also been shown to decrease across life span. In order to investigate the age-related decline in IGF-1 in relation to the structural changes that occur in senescent animals, the present proposal will address the overall hypothesis that the age-related decline in IGF-1 in combination with the accumulated oxidative stress across life span are critical factors in structural changes that take place in the aging brain, in particular, an age-related loss of synapses and/or dendritic spines; furthermore, increased IGF-1 levels will protect synapses and dendritic spines from the biological effects of oxidative stress. Three specific aims will examine the relationship between IGF-1 level and neural connectivity as well as determine what role IGF-1 might play in protecting synapses and spines from oxidative stress.